The Relevance of Minimal Residual Disease (MRD) Monitoring in Elderly Multiple Myeloma (MM) Patients

Introduction: In MM, there is growing body of evidence showing the importance of MRD monitoring particularly among transplant-eligible patients. However, it is perhaps in elderly MM, the major patient subgroup and in which optimal balance between efficacy and toxicity is critical, that sensitive response assessment could help to tailor patients' treatment.

Methods: We used an 8-color second-generation flow assay to monitor MRD among elderly MM patients (n=163) included in the PETHEMA/GEM2010MAS65 trial (sequential chemotherapy with 9 cycles of bortezomib-melphalan-prednisone (VMP) followed by 9 cycles of lenalidomide-low dose dexamethasone (Rd), or alternating cycles of VMP and Rd up to 18 cycles). A single 8-color antibody combination (CD45-PacB/CD138-OC515/CD38-FITC/CD56-PE/CD27-PerCPCy5.5/CD19-PECy7/CD117-APC/CD81-APCH7) was used to detect phenotypically aberrant clonal plasma cells (PCs), and MRD-negativity was defined when <20 clonal PCs were detected among ≥2.000.000 leukocytes (<0.001%; limit of detection: 10^-5). MRD assessment was centralized in three PETHEMA/GEM laboratory-cores, cytometrists were blinded to all clinical data, and results were prospectively uploaded into a locked intranet dataset. Median follow-up was 3-years; time-to-progression (TTP) and overall survival (OS) were measured from diagnosis.

Results: MRD-negative rates at cycle 9 of chemotherapy (n=128) were similar between the sequential vs alternating regimens (20% vs 24%; P=.37). Patients attaining MRD-negativity at cycle 9 showed a significantly prolonged TTP (median not reached -NR- vs 35 months; P =.001) as well as OS (100% vs 72% at 3-years; P=.02) as compared to patients with persistent MRD. Even among patients in complete response at cycle 9 (n=43), MRD-persistence continued to result in significantly inferior OS (100% vs 74% OS at 3-years; P=.02). To understand the kinetics of MRD response with sequential vs alternating 18 cycles of chemotherapy, we focused on patients with paired MRD assessments at cycles 9 and 18. Up to 19% of MRD-positive patients at cycle 9 became MRD-negative at cycle 18, with no significant differences between rates of transformation after sequential vs alternating regimens (P=.28); by contrast, no MRD-negative patients at cycle 9 turned into MRD-positive at cycle 18. At the end of cycle 18 (n=119), MRD-negative rates were slightly higher among patients randomized to the sequential vs alternating schema: 46% vs 33% (P=.19). In contrast to previous studies in which MRD assessment has been performed at intermediate stages of patients' treatment (eg: before maintenance), the design of the GEM2010MAS65 trial allowed to investigate the immediate impact in patients' outcome according to their depth of response without additional (maintenance) therapy. Thus, whereas the median TTP was not reached for patients in CR plus MRD-negativity, it became significantly shorter for cases in CR and less than CR but remaining MRD-positive (42 vs. 30 months, respectively; P<.001). Afterwards, we also compared the impact of MRD-negativity among cytogenetically defined standard- and high-risk t(4;14), t(14;16), and del(17p)] patient subgroups (total of 132). As expected, standard-risk patients attaining MRD-negativity had significantly prolonged TTP as compared to MRD-positive patients (median 40 vs 31 months; P =.002); interestingly, also high-risk cytogenetic patients reaching MRD-negativity showed significantly superior time-to progression (median NR vs 26 months; P=.007). Lastly, we assessed if the impact of attaining MRD-negativity was equally beneficial according to patients' age. Interestingly, while median TTP was not reached for patients with 65-75 and 75-80 years reaching MRD-negativity, it became of 32, 28 and 22 months for MRD-positive patients with 65-75 vs 75-80 vs >80 years, respectively (P<.001). Only 2 cases older than 80 years old reached MRD-negativity (both relapse-free).

Conclusions: Here, we show the clinical impact of depth of response including MRD-negativity in elderly MM patients, which translated into significantly improved survival irrespectively of patients' age and cytogenetic risk. Conversely, patients with standard-risk MM as well as those in CR but remaining MRD-positive experience poor outcomes, and warrant potential treatment individualization to improve their survival.